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GOUT AND CARDIOVASCULAR DISEASE
959 HYPERNATRÆMIA AND ACIDOSIS IN ASSOCIATION WITH TOPICAL TREATMENT OF BURNS
SIR,—While fluid and electrolyte disturbances are major in patients with burns, it is not always appreciated that certain forms of topical therapy may contribute to these problems.’ Povidone-iodine ointmcnt (’Betadine’) has been advocated for topical treatment of burns;2 it is generally regarded as a safe compound3but severe hypernatraemia and
problems
acidosis may occur. A 20-year-old 45
kg nursing student was admitted with 35%
, second-degree burns of the head,
arms, and upper torso sustained in a house fire. Topical therapy with 2.6-3.2kg of povidone-iodine ointment was started immediately. Over the next 6 days she remained afebrile and normotensive. 12 h after the
start of topical therapy, she was noted to be persistently hypernatraemic and hyperosmolar (see figure) with serum-sodium values of 149-154 mmol/l and serum osmolalities of 360-365 mosmovi while receiving 5-9 litres of 5% dextrose in water intravenously daily. Coincident with this, the patient was persistently acidotic (arterial pH 722-730) despite adequate oxygenation and intravenous sodium bicarbonate. Blood-ureanitrogen was 19-45 mg/dl serum-creatinine 1 - 1- 1 .99 mg/dl, serum-potassium 3-0-4-2 mmol/l, serum-chloride 111-114
sodium, arterial pH, and serum osmolality response topical therapy with povidone-iodine.
Serum
to
mmot/1 and serum-bicarbonate 13-17 mmoi/L Serum-lactate levels ranged from 5 to 16-5 mmoVl. Serum-protein-boundiodine was greater than 30 mmol/dl. On the seventh hospital
day topical povidine-iodine ointment was stopped and silver sulphadiazine was substituted. Within 24 h, serum-sodium fell to 138 mmol/l and arterial pH rose to 7-36 with no further bicarbonate therapy. The patient’s electrolyte and acid-base problems then remained easily controlled until she died 15 days later with disseminated intravascular coagulation. We have seen three additional patients with unexplained hypematraemia and acidosis in association with topical treatment of burns with povidone-iodine. We believe that this form of therapy played a significant role in the development of these profound metabolic abnormalities. Povidone-iodine ointment an osmolality in excess of 1000 mosmol/l, thus allowmg a strong osmotic gradient to be established between areas of topical application and the patient. As a consequence, free water is lost with subsequent intravascular dehydration and hypernatrsemia. Lacticacidosis may result as a consequence of tissue ischæmia,4 decreased lactate extraction by the liver,5 or
possesses
1 2
Moncrief, M. A. New Engl. J. Med. 1973, 288, 444. Georgiade, N. G., Harris, M. A. Plast. reconstr. Surg. 1973, 52, 680.
3. Lancet, 1976, i, 73. 4. Oliva, P. B. Am. J. Med. 1970, 48, 209. 5 Berry, M. N. Proc. Roy. Soc. Med. 1967,
60, 1260.
intracellular dehydration.6 Povidone-iodine itself may lead to metabolic acidosis.7 While serum-iodine levels were not measured in our patient, it is possible that acidosis was a result of hyperosmolality, hypovolsemia, and a direct effect of povidoneiodine. These complications of topical povidone-iodine seem to be limited to patients with second-degree burns. This may be explained by the fact that such patients, unlike patients with third-degree burns, have no protective eschar. Thus, water can pass freely between ointment and patient. We feel that topical povidone-iodine ointment, especially when used in patients with second-degree burns, may well contribute to the electrolyte and acid-base disturbances seen in burn patients. Physicians should be aware of this potential
complication. C.S. is
a
teaching and research scholar of the American College of
Physicians. Department of Medicine, University of Colorado Medical Center, Denver, Colorado 80262, U.S.A.
CHARLES SCOGGIN JOSEPH R. MCCLELLAN JEFFREY M. CARY
GOUT AND CARDIOVASCULAR DISEASE
SIR,-An epidemiological association between gout and cardiovascular disease has long been known, but attempts to demonstrate that the association results from the high plasmauric-acid concentrations affecting thrombus formation have produced equivocal results. In view of the central importance of platelets in the formation of arterial thrombi work has concentrated on the effect of uric acid on platelet function. Disagreements occur in epidemiological studies, in experiments with intravenous injections of uric acid or the addition of uric acid to blood in vitro, and in the study of platelets from patients with gout. By feeding rats diets rich in nucleic acid and including oxonate, a specific uricase inhibitor, we have induced a continuous hyperuricaemic condition that seems to be more analogous to human hyperuricxmia than are other animal models. The hyperuricaemia is induced long term without the complications of genetically determined gout-an important featur because the association between raised uric-acid concentrations and the risk of coronary heart-disease disappears when data from patients with clinically overt gout are removed.1 We have observed a significant increase in platelet aggregation induced either by A.D.P. or by thrombin in platelet-rich plasma from hyperuricæmic animals compared with controls, and there was a significant correlation between the plasmauric-acid and platelet aggregation.’ Whole-blood platelet-count was also increased in hyperuricmmic animals, which might further enhance the risk of aggregation in vivo. Further experiments have shown that there is a linear relationship between the nucleic-acid content of the diet and platelet aggregation; and a time-lag exceeding the lifespan of the platelets was observed between the development of hyperuricsemia and the increase in aggregation,’ 4 suggesting that uric acid exerted its effect, not on circulating platelets, but, more probably, at a site of platelet production. We also observed a striking increase in the amount of uric acid in the kidney in the hyperuricwmic animals, and histological studies showed that the uric-acid deposits were concentrated within the tubules in the pyramid region. The kidneys of the hyperuricæmic animals were 40% heavier, a change attributable mainly to hypertrophy. These findings might explain the association between gout 6. Sotos, J. F., Dodge, P. R., Talbot, N. B. Pediatrics, 1962, 30, 180. 7. Pietsch, J., Meakins, J. L. Lancet, 1967, i, 280. 1. Hall, A. P. Arthritis Rheum. 1965, 8, 846. 2. Winocour, P. D., Munday, K. A., Taylor, T. G., Turner, M. R. Proc. Nutr. Soc. 1976, 35, 54A. 3. Winocour, P. D., Munday, K. A., Taylor, T. G., Turner, M. R. ibid. 1977, 36, 89A. 4. Winocour, P. D., Turner, M. R., Taylor, T. G., Munday, K. A. Unpublished.
960 and cardiovascular disease, and would suggest that people at risk of ischsemic heart-disease should avoid diets high in nuc-
leic-acid content. P. D. WINOCOUR M. R. TURNER T. G. TAYLOR K. A. MUNDAY
Department of Physiology and
Biochemistry, University of Southampton, Medical and
Biological Sciences Building,
Southampton SO9 3TU
DIAGNOSIS OF EXOCRINE PANCREATIC DISEASE BY SYNTHETIC PEPTIDE
SIR,-Arvanitakis and, Greenberger reported their results with
diagnostic test of exocrine pancreatic function.’1 Chymotrypsin catalyses the hydrolysis of orally ingested N-benzoyl-L-tyrosyl-p-aminobenzoic acid. p-aminobenzoic acid (P.A.B.A.) is liberated in the small bowel, absorbed, conjugated by the liver, and excreted into the urine. The quantity of P.A.B.A. in the urine reflects pancreatic chymotrypsin activity. We have studied ten healthy males aged 23-31 and nine patients with chronic pancreatitis. All patients were chronic alcoholics with a history of recurrent bouts of abdominal pain typical of pancreatitis and one or more of the following: steatorrhcea (three out of four tested), pancreatic calcifications by X-ray (four), pancreatic pseudocyst by X-ray, abdominal ultrasound, or surgery (two), or confirmation of chronic pana new
MEAN
(AND RANGE) CUMULATIVE %
URINARY P.A.B.A. RECOVERED AS
OF ADMINISTERED DOSE
HOURS AFTER ORAL DOSE Mean cumulative recovery of urinary P.A.B.A. for controls (I) and patients with pancreatitis (0). The dashed lme is the difference between the means for controls and
patients.
Background (control) concentrations negligible. *Mann-Whitney ranking test.
of urinary aromatic amines
were
creatitis at laparotomy (one). Four patients were studied electively and five during convalescence after a bout of abdominal pain. Total urine volume was collected at intervals of 4, 8, 12, and 24 h during a control period and again after oral administration of lg of the test peptide. The urinary concentration of aromatic amines was determined at Warren-Teed Laboratories by the method of Bratton-Marshal as modified by Smith et aI.2 The mean (and range) cumulative percent recovery of the administered dose was determined for each collection interval (see table). Differences between the two groups were 21, 25, 23, and 23% at 4, 8, 12, and 24 h, respectively (see figure), and were significant although there was some overlap. The 8 h cumulative values for two patients (71%, 75.1%) lay within the normal range. One of these patients had a normal fat output (6 g/day), and a. pseudocyst had resolved spontaneously one year earlier. The other patient had a pseudocyst of the tail of the pancreas, but stool fat was not measured. There was no objective evidence of pancreatic insufficiency in either patient. The six patients with pancreatic calcification and/or steatorrhcea had significantly less urinary excretion of aromatic amines after ingestion of the peptide (p<0.05) than did the other three patients. No adverse effects were noted in patients or controls. Postdose laboratory values (liver-function tests, blood-count, urinalysis) did not differ from pre-dose values which were
largely normal. These results confirm the work of Arvanitakis and Greenberger’ and suggest that the test may be useful in detecting 1. 2.
Arvanitakis, C., Greenberger, N. J. Lancet, 1976, i, 663. Smith, H. W., Finkelstein, N., Aliminosa, L., Crawford, B., Graber, M. J. clin. Invest.
1945, 24, 388.
pancreatic exocrine dysfunction. Salway and Payne3 suggested that substrate exhaustion caused the overlap in P.A.B.A. excretion between controls and patients with pancreatitis and that increasing the dose might give better discrimination. We agree. R. A. RITTGERS Mallory Gastrointestinal Boston City Hospital,
Research
Laboratory,
Boston, Massachusetts 02118, U.S.A.
A. E. FEINERMAN M. S. LOEWENSTEIN N. ZAMCHECK
CROMOGLYCATE IN ASTHMA
SIR We were interested in the comparison of cromogly(’Intal’) with theophylline in children with asthma reported by Dr Hambleton and his colleagues (Feb. 19, p. 381) cate
but are unhappy with their conclusions. Our experience of a comparison of cromoglycate with an oral antiallergic compound, doxantrazole, has impressed on us the difficulty of selecting patients for such trials. In comparing cromoglycate with another drug in the prophylaxis of asthmatic symptoms it is important to know whether the patients are cromoglycate responders, since studies of children’ and adults2 have shown that only 50-70% of asthmatic patients gain definite benefit from cromoglycate. If the aim of a trial is to see if the new drug is as effective as cromoglycate then the proportion of patients who respond to cm moglycate must be known. Hambleton et al. state that all 13
of the children from the Hammersmith were "previously judged acceptably controlled on cromoglycate". Their table suggests that 6 of the 13 children had symptoms on 68% or more days on cromoglycate and 2 required an increased number of emergency treatments. Would these 6 children still 3. Salway, J. G., Payne, R. B. Lancet, 1976, ii, 100. 1. Silverman, M., Connolly, N. M., Balfour-Lynn, L., Godfrey, S. Br. 1972, iii, 378. 2. Brompton Hospital/M.R.C. Collaborative Trial. ibid. 1972, iv, 383.
med.J
SIR,—While fluid and electrolyte disturbances are major in patients with burns, it is not always appreciated that certain forms of topical therapy may contribute to these problems.’ Povidone-iodine ointmcnt (’Betadine’) has been advocated for topical treatment of burns;2 it is generally regarded as a safe compound3but severe hypernatraemia and
problems
acidosis may occur. A 20-year-old 45
kg nursing student was admitted with 35%
, second-degree burns of the head,
arms, and upper torso sustained in a house fire. Topical therapy with 2.6-3.2kg of povidone-iodine ointment was started immediately. Over the next 6 days she remained afebrile and normotensive. 12 h after the
start of topical therapy, she was noted to be persistently hypernatraemic and hyperosmolar (see figure) with serum-sodium values of 149-154 mmol/l and serum osmolalities of 360-365 mosmovi while receiving 5-9 litres of 5% dextrose in water intravenously daily. Coincident with this, the patient was persistently acidotic (arterial pH 722-730) despite adequate oxygenation and intravenous sodium bicarbonate. Blood-ureanitrogen was 19-45 mg/dl serum-creatinine 1 - 1- 1 .99 mg/dl, serum-potassium 3-0-4-2 mmol/l, serum-chloride 111-114
sodium, arterial pH, and serum osmolality response topical therapy with povidone-iodine.
Serum
to
mmot/1 and serum-bicarbonate 13-17 mmoi/L Serum-lactate levels ranged from 5 to 16-5 mmoVl. Serum-protein-boundiodine was greater than 30 mmol/dl. On the seventh hospital
day topical povidine-iodine ointment was stopped and silver sulphadiazine was substituted. Within 24 h, serum-sodium fell to 138 mmol/l and arterial pH rose to 7-36 with no further bicarbonate therapy. The patient’s electrolyte and acid-base problems then remained easily controlled until she died 15 days later with disseminated intravascular coagulation. We have seen three additional patients with unexplained hypematraemia and acidosis in association with topical treatment of burns with povidone-iodine. We believe that this form of therapy played a significant role in the development of these profound metabolic abnormalities. Povidone-iodine ointment an osmolality in excess of 1000 mosmol/l, thus allowmg a strong osmotic gradient to be established between areas of topical application and the patient. As a consequence, free water is lost with subsequent intravascular dehydration and hypernatrsemia. Lacticacidosis may result as a consequence of tissue ischæmia,4 decreased lactate extraction by the liver,5 or
possesses
1 2
Moncrief, M. A. New Engl. J. Med. 1973, 288, 444. Georgiade, N. G., Harris, M. A. Plast. reconstr. Surg. 1973, 52, 680.
3. Lancet, 1976, i, 73. 4. Oliva, P. B. Am. J. Med. 1970, 48, 209. 5 Berry, M. N. Proc. Roy. Soc. Med. 1967,
60, 1260.
intracellular dehydration.6 Povidone-iodine itself may lead to metabolic acidosis.7 While serum-iodine levels were not measured in our patient, it is possible that acidosis was a result of hyperosmolality, hypovolsemia, and a direct effect of povidoneiodine. These complications of topical povidone-iodine seem to be limited to patients with second-degree burns. This may be explained by the fact that such patients, unlike patients with third-degree burns, have no protective eschar. Thus, water can pass freely between ointment and patient. We feel that topical povidone-iodine ointment, especially when used in patients with second-degree burns, may well contribute to the electrolyte and acid-base disturbances seen in burn patients. Physicians should be aware of this potential
complication. C.S. is
a
teaching and research scholar of the American College of
Physicians. Department of Medicine, University of Colorado Medical Center, Denver, Colorado 80262, U.S.A.
CHARLES SCOGGIN JOSEPH R. MCCLELLAN JEFFREY M. CARY
GOUT AND CARDIOVASCULAR DISEASE
SIR,-An epidemiological association between gout and cardiovascular disease has long been known, but attempts to demonstrate that the association results from the high plasmauric-acid concentrations affecting thrombus formation have produced equivocal results. In view of the central importance of platelets in the formation of arterial thrombi work has concentrated on the effect of uric acid on platelet function. Disagreements occur in epidemiological studies, in experiments with intravenous injections of uric acid or the addition of uric acid to blood in vitro, and in the study of platelets from patients with gout. By feeding rats diets rich in nucleic acid and including oxonate, a specific uricase inhibitor, we have induced a continuous hyperuricaemic condition that seems to be more analogous to human hyperuricxmia than are other animal models. The hyperuricaemia is induced long term without the complications of genetically determined gout-an important featur because the association between raised uric-acid concentrations and the risk of coronary heart-disease disappears when data from patients with clinically overt gout are removed.1 We have observed a significant increase in platelet aggregation induced either by A.D.P. or by thrombin in platelet-rich plasma from hyperuricæmic animals compared with controls, and there was a significant correlation between the plasmauric-acid and platelet aggregation.’ Whole-blood platelet-count was also increased in hyperuricmmic animals, which might further enhance the risk of aggregation in vivo. Further experiments have shown that there is a linear relationship between the nucleic-acid content of the diet and platelet aggregation; and a time-lag exceeding the lifespan of the platelets was observed between the development of hyperuricsemia and the increase in aggregation,’ 4 suggesting that uric acid exerted its effect, not on circulating platelets, but, more probably, at a site of platelet production. We also observed a striking increase in the amount of uric acid in the kidney in the hyperuricwmic animals, and histological studies showed that the uric-acid deposits were concentrated within the tubules in the pyramid region. The kidneys of the hyperuricæmic animals were 40% heavier, a change attributable mainly to hypertrophy. These findings might explain the association between gout 6. Sotos, J. F., Dodge, P. R., Talbot, N. B. Pediatrics, 1962, 30, 180. 7. Pietsch, J., Meakins, J. L. Lancet, 1967, i, 280. 1. Hall, A. P. Arthritis Rheum. 1965, 8, 846. 2. Winocour, P. D., Munday, K. A., Taylor, T. G., Turner, M. R. Proc. Nutr. Soc. 1976, 35, 54A. 3. Winocour, P. D., Munday, K. A., Taylor, T. G., Turner, M. R. ibid. 1977, 36, 89A. 4. Winocour, P. D., Turner, M. R., Taylor, T. G., Munday, K. A. Unpublished.
960 and cardiovascular disease, and would suggest that people at risk of ischsemic heart-disease should avoid diets high in nuc-
leic-acid content. P. D. WINOCOUR M. R. TURNER T. G. TAYLOR K. A. MUNDAY
Department of Physiology and
Biochemistry, University of Southampton, Medical and
Biological Sciences Building,
Southampton SO9 3TU
DIAGNOSIS OF EXOCRINE PANCREATIC DISEASE BY SYNTHETIC PEPTIDE
SIR,-Arvanitakis and, Greenberger reported their results with
diagnostic test of exocrine pancreatic function.’1 Chymotrypsin catalyses the hydrolysis of orally ingested N-benzoyl-L-tyrosyl-p-aminobenzoic acid. p-aminobenzoic acid (P.A.B.A.) is liberated in the small bowel, absorbed, conjugated by the liver, and excreted into the urine. The quantity of P.A.B.A. in the urine reflects pancreatic chymotrypsin activity. We have studied ten healthy males aged 23-31 and nine patients with chronic pancreatitis. All patients were chronic alcoholics with a history of recurrent bouts of abdominal pain typical of pancreatitis and one or more of the following: steatorrhcea (three out of four tested), pancreatic calcifications by X-ray (four), pancreatic pseudocyst by X-ray, abdominal ultrasound, or surgery (two), or confirmation of chronic pana new
MEAN
(AND RANGE) CUMULATIVE %
URINARY P.A.B.A. RECOVERED AS
OF ADMINISTERED DOSE
HOURS AFTER ORAL DOSE Mean cumulative recovery of urinary P.A.B.A. for controls (I) and patients with pancreatitis (0). The dashed lme is the difference between the means for controls and
patients.
Background (control) concentrations negligible. *Mann-Whitney ranking test.
of urinary aromatic amines
were
creatitis at laparotomy (one). Four patients were studied electively and five during convalescence after a bout of abdominal pain. Total urine volume was collected at intervals of 4, 8, 12, and 24 h during a control period and again after oral administration of lg of the test peptide. The urinary concentration of aromatic amines was determined at Warren-Teed Laboratories by the method of Bratton-Marshal as modified by Smith et aI.2 The mean (and range) cumulative percent recovery of the administered dose was determined for each collection interval (see table). Differences between the two groups were 21, 25, 23, and 23% at 4, 8, 12, and 24 h, respectively (see figure), and were significant although there was some overlap. The 8 h cumulative values for two patients (71%, 75.1%) lay within the normal range. One of these patients had a normal fat output (6 g/day), and a. pseudocyst had resolved spontaneously one year earlier. The other patient had a pseudocyst of the tail of the pancreas, but stool fat was not measured. There was no objective evidence of pancreatic insufficiency in either patient. The six patients with pancreatic calcification and/or steatorrhcea had significantly less urinary excretion of aromatic amines after ingestion of the peptide (p<0.05) than did the other three patients. No adverse effects were noted in patients or controls. Postdose laboratory values (liver-function tests, blood-count, urinalysis) did not differ from pre-dose values which were
largely normal. These results confirm the work of Arvanitakis and Greenberger’ and suggest that the test may be useful in detecting 1. 2.
Arvanitakis, C., Greenberger, N. J. Lancet, 1976, i, 663. Smith, H. W., Finkelstein, N., Aliminosa, L., Crawford, B., Graber, M. J. clin. Invest.
1945, 24, 388.
pancreatic exocrine dysfunction. Salway and Payne3 suggested that substrate exhaustion caused the overlap in P.A.B.A. excretion between controls and patients with pancreatitis and that increasing the dose might give better discrimination. We agree. R. A. RITTGERS Mallory Gastrointestinal Boston City Hospital,
Research
Laboratory,
Boston, Massachusetts 02118, U.S.A.
A. E. FEINERMAN M. S. LOEWENSTEIN N. ZAMCHECK
CROMOGLYCATE IN ASTHMA
SIR We were interested in the comparison of cromogly(’Intal’) with theophylline in children with asthma reported by Dr Hambleton and his colleagues (Feb. 19, p. 381) cate
but are unhappy with their conclusions. Our experience of a comparison of cromoglycate with an oral antiallergic compound, doxantrazole, has impressed on us the difficulty of selecting patients for such trials. In comparing cromoglycate with another drug in the prophylaxis of asthmatic symptoms it is important to know whether the patients are cromoglycate responders, since studies of children’ and adults2 have shown that only 50-70% of asthmatic patients gain definite benefit from cromoglycate. If the aim of a trial is to see if the new drug is as effective as cromoglycate then the proportion of patients who respond to cm moglycate must be known. Hambleton et al. state that all 13
of the children from the Hammersmith were "previously judged acceptably controlled on cromoglycate". Their table suggests that 6 of the 13 children had symptoms on 68% or more days on cromoglycate and 2 required an increased number of emergency treatments. Would these 6 children still 3. Salway, J. G., Payne, R. B. Lancet, 1976, ii, 100. 1. Silverman, M., Connolly, N. M., Balfour-Lynn, L., Godfrey, S. Br. 1972, iii, 378. 2. Brompton Hospital/M.R.C. Collaborative Trial. ibid. 1972, iv, 383.
med.J